Performance. concerns?

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1 Performance concerns? There is hardly anything in the world that some man can t make a little worse and sell a little cheaper, and the people who consider price only are this man s lawful prey. John Ruskin

2 ENRADIN is a step above common enramycins. ENRADIN is a proven way to increase feed efficiency. At recommended levels in poultry feed, ENRADIN provides excellent control of bacteria that cause necrotic enteritis and growth depression. Our advanced manufacturing process delivers a product that is safe, stable, homogenous and highly efficacious for your flock. Strictly regulated production. ENRADIN is manufactured by a highly skilled workforce under the Good Manufacturing Practice (GMP), including strict regulatory and MSD Animal Health oversights. Our manufacturing facility is inspected and approved by regulatory authorities from the following countries and regions: Common questions and answers. The story behind ENRADIN: What makes it so different from generic enramycin? With generic enramycins entering the market, we d like to take this opportunity to answer some common questions about the superior value of ENRADIN. Q. Where does ENRADIN come from? A. ENRADIN is produced from fermentation products of Streptomyces fungidicus, isolate B5477 developed in 1966 by Japan Takeda and registered in Japan in The specific master seed stock and the accompanying manufacturing technology were transferred to production facilities at Zhejiang Hisun Pharmaceutical Co., Ltd. (Zhejiang Hisun Pharmaceutical) in China. Japan Takeda Animal Health (now a part of MSD Animal Health) and Zhejiang Hisun Pharmaceutical Company are the only authorized manufacturers of enramycin from the original Takeda B5477 master seed stock. This unique seed culture is essential to the production of enramycin of high potency and consistent molecular quality. Q. How is the production technique of ENRADIN unique? A. Fermentation is a dynamic, changing process of microorganism metabolism. During fermentation, three aspects mycelia growth, fermentation control parameters and formulation speed of the target product have been dynamically changed and correlated. Spray Drying Control US (FDA) EU (EDQM) Germany (BfArM) UK (MRHA) Australia (TGA) Japan (PMDA) South Korea (KFDA) China (SFDA, MOA) Rigorous control and monitoring of ENRADIN production ensures the product s potency and consistency. Q. Why is it important to use this MSD specific seed stock? A. Japan Takeda spent more than 10 years developing the S. fungidicus B5477 seed culture breeding, separation, purification and storage technology. The seed culture was developed to maintain a stable hereditary character. Carefully developed storage technology maintains the original seed culture, ensuring a prolonged life span and no degradation. Bioassay Fermentation Control These processes are automated in the production of ENRADIN, with online sensors to monitor the fermentation growth curve and to optimize key fermentation parameters in three categories: Physical: temperature, pressure, agitation speed, airflow, turbidity, viscosity Chemical: ph and dissolved oxygen Biological: mycelia concentration

3 Q. Once enramycin is produced, isn t it just enramycin? What makes ENRADIN unique? A. All enramycin is not produced equally. Unlike a chemically synthesized product, a fermentation product like ENRADIN contains mycelia cells, culture broth, metabolism by-products and impurities, potentially including heavy metals. The final product is a large, polypeptide macromolecule with two distinct active components, A and B. The A and B molecules differ in molecular weight due to the number of carbon and hydrogen molecules present in their structure. An advanced extraction process is required to ensure the end product is safe, stable, homogenous and highly efficacious. The processes for ENRADIN have been carefully developed and are tested at each step. Spray-drying of the final product ensures that ENRADIN does not remain in contact with heat for a prolonged period, as may occur with fluid bed ( roller ) drying methods. Figure 1: Color and consistency of ENRADIN vs. two generic enramycin products vibration during transportation. A coarse, heavy product can easily settle out of the mash, resulting in poor uniformity of distribution in the finished feed. A product made of fine particles ensures a homogenous mix in the final stages before pelleting in crumble or pellet-feed forms. Q. How is the potency and biological activity of ENRADIN certified? A. The potency and biological activity of ENRADIN is monitored and certified using a culture method based on the only enramycin reference standard in the world: the original Japan Takeda reference standard. The reference standard used by Zhejiang Hisun Pharmaceutical has been certified using the Japan Takeda reference standard. When you buy ENRADIN, you get enramycin at the right potency, plus full MSD Animal Health support and warranty from a solid partner that has been in the molecule development and enhancement business for more than 40 years. Q. When samples of generic products are tested against the recognized reference standard, how do they compare? Generic Enramycin 4 % Figure 2 Generic Enramycin Potency 1 (Acceptable = 90% 110% of Reference Standard Activity) % of expected potentcy Q. Only some of the generic samples are close to the 90% standard, and many others are far below. Is that good enough? A. Not really. Consider the risks of using products below acceptable standard activity levels. The samples themselves show wide variability. 1 How do you know which batch you will receive? Without a reference standard for testing, automated production and careful monitoring of intermediate steps, variability can be expected from generic products. The stability of a generic product is unknown. ENRADIN s stability has been confirmed as per VICH* guideline. Long-term stability study: 36 months, 25 ± 2C, 60% ± 5% Accelerated: 6 months, 40 ± 2C, 75% ± 5% A generic enramycin might also create increased variability for a final product made with coarse particles that may not mix uniformly in the feed, or that do not remain uniformly mixed during transportation. Generic I ENRADIN Generic II ENRADIN is a state-of-the-art form of enramycin. Longer contact with heat results in a darker color and potentially lower potency. See Figure 1 above. The premix is tested to ensure homogeneity and good consistency for mixing in feeds. Q. In the photograph, Figure 1, ENRADIN from MSD appears to have a finer, more powder consistency than the other products. Is this important? A.. Mash feed formulations must undergo a lot of A. The samples demonstrate highly variable activity. 1 This is why GMP manufacturing processes and automation with monitoring of intermediate steps are so important. ENRADIN is always tested against the reference standard. As a result, every batch demonstrates high potency. See Figure 2. Take advantage of more than 40 years of expertise. Bring the value of our state-of-the-art production knowledge to your end products. A feed conversion increase of just 0.01 kg in a 1.6 kg broiler is worth $1.94/1,000 kg of feed at U.S. $300/1,000 kg. Any measurable loss in performance, even 10 grams, is worth more than the difference in drug cost. Generic Enramycin 8 % ENRADIN Data on file, MSD Animal Health Generic Enramycin ENRADIN No other enramycin manufacturer possesses the recognized reference standard of ENRADIN. The potency and biological activity of generic enramycins cannot be reliably measured. The efficacy and long-term stability of ENRADIN have been tested by decades of successful use. ENRADIN is well recognized by producers and nutritionists around the world. It is a brand built on and supported by more than 40 years of experience. Use this advantage to enhance your profitability. ENRADIN is the brand you can trust. *Veterinary International Conference on Harmonization

4 We control process and quality in every way. So you benefit from reliability in every feed mix. ENRADIN Quality and Process Control Quality Procedures GMP training Testing of raw materials 28 raw materials each undergo specific test regimen to ensure safety and quality Testing of finished product Particle size, appearance, identity, potency, contaminants Stability monitoring EM water system monitoring Compressed air system monitoring Lab equipment qualification Validation management Sample/retained sample management Pharmacopeia compliance Reference Standard management Test skill training Deviation and complaint procedures Risk identification and control measures Critical Control Point monitoring schedule Procedure and documentation of cleaning Facilities Equipment Transport vehicles Traceability of raw materials and ingredients Batch number and documentation Check ENRADIN Quality and Process Control Quality System Facility & Equipment System Production System Packaging & Labeling System Laboratory Control System Material Control System GMP Systems Annual product review Auditing program Regulatory inspection Internal GMP audits Audits of suppliers Change control Complaints Product quality complaints GMP verification Deviation management Product release Quality management Reprocess/Rework SOP management GMP training & personnel Cleaning/Housekeeping/ Maintenance Cleaning validation Environment control Facilities & equipment qualification Maintenance/Calibration utilities Documentation Process controls Manufacturing practices Process validation Labeling & packaging component control Packaging control Laboratory instrumentation Sampling and testing Stability Material handling Supplier management Check FEEDING A GROWING WORLD POPULATION CALLS FOR ENHANCED PRODUCTIVITY. AND OUR SCIENCE. The global population is 7 billion and increasing. So the pressure to find more effective strategies to manage resources is immense. To meet the growing demand for protein, we are helping farmers become more efficient and productive. Merck Animal Health s Intestinal Health franchise enhances the health of chickens, enabling more animals to grow to their full potential. By working closely with farmers, we are helping to safeguard the future of our food supplies. Find out more at merck-animal-health.com THE SCIENCE OF HEALTHIER ANIMALS TM

5 RELAX Enjoy superior results that last Enradin s superior activity for Clostridium perfringens and its consistent efficacy make it the leading brand and most effective feed medication for Clostridial Enteritis Intervet International bv - P.O. Box 31, 5830 AA Boxmeer - The Netherlands Phone: +31 (0) Fax: +31 (0) info@intervet.com - R1_ Intervet International B.V., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. PM10_0092